mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Bladder cancer: genetic variation among smokers and non-smokers
Bladder cancer has been shown in the past to have a high correlation with individuals who smoke cigarettes. This GWAS study was taken from a paper entitled: Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers, which was published in 2012. Six SNPs were analyzed in this study that were previously found to be associated with urinary bladder cancer. In this study, 1,595 patients with bladder cancer were compared with 1,760 controls. Variations of rs1014971, rs11892031, rs1495741, rs710521, rs8102137, rs9642880, as well as GSTM1 were the focus of the study. Previously, rs1014971 has been shown to be located in a non-genic portion of chromosome 2q13.1, in close proximity to APOBEC3 [2]. Rs11892031 resides on chromosome 2q37 in the UGT1A locus. UGT1A is important for removing foreign chemicals in organisms. Rs149571 is located on chromosome 8p22 and is important for telling the difference between fast and slow acetylation. Slow acetylation has been correlated with increased odds of developing bladder cancer, probably due to improper detoxification. Rs710521 is found on chromosome 3q28, and is in close proximity to TP63. TP63 has been shown to be affiliated with a risk for bladder cancer. Rs8102137 is found on chromosome 19q12 and is involved with progression of the cell cycle. Rs9642889 is on chromosome 8q24.21, very close to the MYC gene, which is an established proto-oncogene [2]. The deletion of GSTM1, or glutathione-S-transferase M1 has also been shown to increase the risk of bladder cancer development [1 ]. This enzyme is located on chromosome 1q13.3, and deletion of this gene reduces the ability of foreign chemicals in the body to be detoxified. The gene is therefore also an interesting candidate in the studies done by Schwender et al. in 2012. Altogether, previous GWAS studies have identified GSTM1, along with the six SNPs described, in association with bladder cancer. The study by Schwender et al. aims to tease apart these SNPs further and determine whether certain combinations of these SNPs lead to increases in bladder cancer susceptibility. Furthermore, the GWAS study asks whether combinations of these SNPs differ between individuals who smoke versus those that do not smoke. Method GSTM1 and the six SNPs were genotyped through the isolation of leukocyte DNA. Genotypes were obtained using a TaqMan assay. To detect whether there was a GSTM1 deletion, primers were used to PCR amplify the region, followed by gel electrophoresis for DNA detection. Findings Single-nucletotide polymorphism combinations differed between smokers and non-smokers. Moreover, former smokers showed a combinatory pattern of polymorphisms of smokers as well as non-smokers. SNPs associated with smoker patient samples were mostly associated with processes important for detoxifying carcinogens. This is depicted in Table 1. On the other hand, SNPs in non-smokers mostly involved processes important for stabilizing DNA, or control of the cell cycle, which is depicted in Table 2. In particular for smokers, deletion of GSTM1 was high scoring, which is involved in detoxification processes. The rs11892031 SNP also scored highly in smokers, which is close to UGT1A. This enzyme is crucial for detoxifying carcinogen-producing agents found in cigarette smoke (which can cause bladder cancer). In non-smokers, SNPs in rs9642880 were more prevalent, which is in close proximity to the MYC gene, which is important for controlling certain genes involved in proliferation. These results raise suggestions that increased susceptibility in non-smokers may be involved with deregulation of factors like cell proliferation. Increasing number of SNPs does not seem to increase the odds ratio of susceptibility to obtain bladder cancer. The odds ratio of developing bladder cancer by smoking is high, at around 3.5 [2 ]. However, odds ratios from SNPs analyzed in this study were only around 2.0, and there was not much of an additive effect with an increasing number of polymorphisms (depicted in Tables 1 and 2). With this knowledge, it seems that environmental components such as smoking have a greater influence in urinary bladder cancer development compared to genetic variation through SNPs. References [1 Bell D., Taylor J., Paulson D., Robertson C., Mohler J., and Lucier G. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst 1993 (14) 1159-64.] [2[2 Schwender H., Selinski S., Blaskewicz M., Marchan R., Ickstadt K., Golka K., and Hengstler J. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLOS One 2012 (12) 1-12.]